The major thrust of this application continues to aim at targeting invariant non-translated domains at the 5'-end of the HIV genome with specifically designed polyamide nucleic acids (PNAs) and their derivatives. The ability of these genome specific antisense inhibitors to block various steps of viral replication will be assessed in order to develop effective multiprong drugs of high therapeutic index. The proposal has five specific aims: Aim 1- To target the primer binding site (PBS) region A- loop region and the stem-loop bulge structure of the viral genome, block their interaction with tRNA3Lys and thus inhibit reverse transcription; Aim 2 - To target the repeat region (R) of the LTR and the att site on the 5' and 3' LTR of the HIV genome to prevent the strand transfer reaction and integration of the proviral genome; Aim 3 - To target the TAR region of the viral RNA genome to prevent its interaction with regulatory transactivating Tat protein; Aim 4 - To develop an effective biodelivery system for promising antisense PNAs; and Aim 5 - To evaluate the in vitro anti viral efficacy and cytotoxicity of the lead PNA compounds in MT-2 cell cultures infected with HIV-1.